Abstract People infected with HIV can expect a near normal life on antiretroviral therapy. In the United States, cancer has become the leading cause of death in the aging HIV-positive population. This includes the AIDS- defining cancers Kaposi sarcoma (KS) and lymphomas, such as primary effusion lymphoma (PEL). In fact, KS is the leading cause of death in the HIV-positive population today. Furthermore, as the HIV-positive cohort ages they are at an increasing risk of developing KS, which is age dependent even in HIV-negative KSHV-carriers. We, and others, have shown that KS and AIDS-associated lymphomas are highly dependent on the PI3K/Akt/mTOR signaling pathway for survival. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that is a downstream target of the PI3K and Akt kinases. Rapamycin is an allosteric inhibitor of the mTORC1 complex and we conducted the first clinical trial of rapamycin in the context of HIV infection. We showed that rapamycin was efficacious in mouse models of KS and PEL and that rapamycin exhibited a direct anti-tumor effect independent of immune modulation. In this application, we propose to investigate additional targets in the PI3K/Akt/mTOR pathway in KSHV cancers, as a model of HIV-associated cancers that are critically dependent on this pathway for their survival. We propose to identify efficacious drug combinations and to delineate the molecular mechanism of different therapeutic targets. This will uncover the next generation of therapies against KS and lymphoma in the context of HIV infection. Since PI3K/Akt kinases have also been shown to be required for optimal HIV infection and replication, we will also test these therapies against HIV replication. Importantly, we will mostly evaluate drugs that have passed human phase I safety trials and thus will be immediately available for clinical trials for HIV-associated KS and lymphomas.